Polyimide microparticles

ABSTRACT

The invention relates to a polyimide microparticles which can be obtained by means of the following steps: a) a polymer solution consisting of at least one polyimide polymer and a solvent or a solvent mixture is produced according to methods known per se, b) microparticles are formed from the polymer solution by spraying or by thermal phase inversion, c) the microparticles obtained in step b) are treated with an aqueous functionalization solution containing an amine-containing modifier at a high temperature, with or without stirring, and d) the modified obtained are washed and optionally dried, according to methods known per se.

This is a Continuation-In-Part Application of International ApplicationPCT/DE2003/002879 filed Aug. 30, 2002 and claiming the priority ofGerman application 102 45 545.7 filed Sep. 30, 2002.

BACKGROUND OF THE INVENTION

The invention relates to polyimide carrier matrices, a method ofmanufacturing the articles and to their use.

Methods for the manufacture of particulate carrier matrices (membranes)with different separating profiles are known and commercially availableon the basis of various polymers. Methods for their manufacture areknown to the person skilled in the art and are based in practice onbasic principles which will be shortly described below:

Preformed polymers preferably of natural or semi-synthetic origin whichalready have chemical functions for the attachment of ligands, aredissolved in an aqueous solvent. The solution is dispersed in a liquidwhich is not mixable with this polymer solution. The solution dropletsare then solidified for example by netting or other chemical or physicalprocesses to form micro-particles.

Under these conditions, the polymer solution is transformed to sphericalsolution droplets by dispersion in a non-mixable organic medium in asimple manner. Basic conditions for the application of this basicprocedure are good dispersion capability of the polymer solutionpossibly supported by surface active substances in the dispersionmedium. The applicability is therefore limited to the dispersion ofaqueous polymer solutions in a hydrophobic organic dispersion medium or,respectively, in a chlorinated hydrocarbon; consequently, only watersoluble polymers can be used as matrix former. With additives and thekind of solidification, the pore profile of the support matrix so madeor, respectively, the microparticles can be affected but the oftenrequired coarse pore structure with high pore density at the particlesurface is not obtained.

Furthermore, basically gel-like support matrices are formed whose porestructure is formed exclusively by swelling of the particle. Permanentlyporous support matrices can basically not be manufactured by thismethod. Depending on the amount of fixation, highly swelled andtherefore easily deformable matrices are formed which are compressedwhen subjected to economical high flow passage rates and then have ahigh flow resistance. The use of low-swelling synthetic polymers whichare preferably soluble in polar or aprotic solvents is not possible withthis method because of the unfavorable mixing conditions with dispersingsystems although interesting property profiles can be expected. Examplesof support matrices which are manufactured in accordance with theprinciple, are Sepharose-types TM (preferably manufactured from nettedAgarose) and cellulose beads.

A second basic method is based on the use of chemically different,usually hydrophobic, monomers which can be polymerized and which aredispersed together with a polymerization initiator and with additives(chemically very different, organo-soluble, but water insolublesubstances) in a non-mixable liquid, preferably water, possibly with theaddition of surface active compounds. The monomer/addition-droplets ofthe dispersions formed in the process are subsequently solidified by anetted precipitation polymerization thereby forming microparticles.During this precipitation polymerization process generally permanentporous support matrices of synthetic netted polymers with littleswelling are formed in aqueous media. Characteristic is that the polymeris built in the process of the particle manufacture. Many possibilitiesof influencing the porosity of the microparticles formed are describedin the literature. In a special embodiment, the dispersed droplets ofthe organic phase are solidified before the polymerization andpolymerized in that state.

The second basic method for the manufacture of support matrices howeveris not applicable if polymers, which have already been synthesized, areto be formed into microparticles. In accordance with this dispersionprinciple organo-soluble monomers with hydroxyl- amino- and/or carboxylfunctions must be selected which significantly limits the content ofchemical functions for the binding of affinity ligands. For generatingor, respectively increasing, the binding functions capable of coupling,such carrier matrices must be provided, before the application, withcorresponding chemical functions to make binding functions available insufficient quantities. This again requires often the use of aggressivemedia and harsh after treatment conditions.

Finally, a third basic process is known whereby microparticles can beproduced from polymer solutions in analogy to a thermal phase inversionduring the formation of the membrane. For realizing this basic process,a solvent mixture and a suitable dispersion medium must be found whichcorresponds to the described behavior. To this end, from the polymer tobe deformed a polymer solution is formed at a raised temperaturewherein, upon controlled cooling to room temperature, the polymersolution is subject to a phase inversion. When such a polymer solutionis dispersed in a phase-forming dispersion medium (micro-dropletformation) and the dispersion is subsequently cooled, a fixed, generallyporous, micro-particle is formed.

In principle, it should be possible to form in accordance with thisthird basic process low-swell carrier matrices of synthetic polymersand, dependent on the polymer used, chemical groups which can befunctionalized. It is however a disadvantage of this third basic processthat it is difficult to control the process so as to obtain particles ofthe respective particle size and to find correspondingsolution/dispersion systems. Furthermore, the formed particles have anouter surface with relatively little porosity. The pore inlets have asmall pore diameter which makes it difficult for large-volume moleculesto enter the particles.

Such particles therefore have little adsorption capacity for largemolecule volume substances in spite of a relatively large inner surface.

In all these manufacturing methods, an interface area is establishedbetween the particles being formed and the liquid or gaseous surroundingarea which, for energetic reasons, changes the surface of the particlebeing formed in such a way that a surface layer of little porosity, thatis with a small number of pores and small pore sizes, is established.The interface layer limits the accessibility of the inner pore system ofthe particles. By swelling of the whole particle (utilization of thebasic principle 1) the surface porosity can be moderately, but notsufficiently, increased which however brings along the disadvantage of acompression instability of the carrier matrix with the passage of aliquid.

Carrier matrices of synthetic organic polymers can be manufactured inaccordance with the earlier presentation only conditionally inaccordance with the third basic method, if, for dissolving the polymerforming the carrier matrix, polar aprotic solvents or mixtures of suchsolvents must be used. Suitable solvents can be formed but not suitabledispersion media. Still, if a sufficient number of groups of thepolymers to be formed into particles which can be functionalized ispresent, which however is not necessarily true particularly inconnection with these polymers, there is the above describeddisadvantage of a small surface porosity. This is particularly grave if,like in the immune-adsorption, large-volume molecules are to be removedfrom the medium by adsorption on a suitable functionalized carriermatrix.

It is furthermore known that polyimides can be chemically changed byamine modification. EP-A 0 401 005 describes the use of aminemodifications for the netting of polyimide gas separation membranes in aheterogeneous reaction. In DE-A 41 175 01, the modification of polyimidesolutions with amine modifications utilizing a homogeneous reaction inorder to increase the viscosity of the polyimide significantly isdescribed. Patents of the Applicants disclose methods of functionalizingpolyimides in homogeneous (DE-A 101 11 663) and in heterogeneous (DE-A101 11 665) reactions, which are so performed that, in both cases, acontrollable, particularly a large, number of freely available chemicalfunctions is obtained which can be used for adsorption separations inthat form or after further conversions.

The state of the art concerning the presently available matrices ispresented in a publication by Suoeka (Present status of apheresistechnologies, Part 3: Adsorbents, Therapeutic Apheresis 1 (1997)271-283). Applications of particular carriers in the chromatography arediscussed by Hermanson et al. (Immobilized Affinity Ligand Techniques,Academic Press Inc., San Diego, New York, Boston, London, Sidney, Tokyo,Toronto, 1992, pp. 1-50). Newest developments of carrier matrices arefurthermore discussed extensively in a publication by Leonard (Newpacking materials for protein chromatography, J. Chromatog. B 699[1997], 3-27.

It is the object of the present invention to separate low-swell, highlyporous microparticles with a high surface porosity and a large porediameter for the formation of large-volume molecules with highselectivity, speed and capacity, and a method for the manufacturethereof.

SUMMARY OF THE INVENTION

The invention relates to a polyimide microparticles which can beobtained by means of the following steps: a) a polymer solutionconsisting of at least one polyimide polymer and a solvent or a solventmixture is produced according to methods known per se, b) microparticlesare formed from the polymer solution by spraying or by thermal phaseinversion, c) the microparticles obtained in step b) are treated with anaqueous functionalization solution containing an amine-containingmodifier at a high temperature, with or without stirring, and d) themodified micro-particles obtained are washed and optionally dried.

It has surprisingly been found that functionalized microparticles whichmay also be called particulate carrier matrices can be provided frompolyimides with the complex characteristics described. To this end, in afirst process step microparticles of polyimides are manufactured. Inthis process step a), a polymer solution of a polyimide polymer or ofseveral polyimide polymers and a solvent or a solvent mixture isproduced in a manner known per se. Consequently, in accordance with theinvention 1, 2, 3, 4 . . . that is many polyimide polymers and also 1,2, 3, . . . that is many solvents can be used.

In a second method stage, that is, in the stage b), the polymer solutionis converted, by spraying or by thermal phase inversion, tomicroparticles in a way known per se.

The micro-particles obtained in step b) are treated in a wet chemicalprocess with an aqueous functionalization solution which contains anamine-containing modifier. This treatment results in an opening of thepore system of the microparticles, particularly of the particle surfacewith a concurrent functionalization of the inner and outer surfaces.

The polyimide microparticles obtained in step c) can be cleaned in stepd) in a manner known per se by washing or another way and, ifappropriate, can be dried.

If it should be necessary to increase the proportion of chemical groupsthat can be functionalized and/or other chemical groups, an additionalmethod step c2) can be performed. In this stage c2), the microparticlesobtained after performing the step c) are treated, after removal of theamine-containing modifier of the method step c) with an aqueousfunctionalization solution which contains at least another modifier.This additional modifier consists of a compound or of 2, 3 . . . or manycompounds with at least two functional groups of which one group is anamine group.

The additional modifier employed in the method step c2) furthermoreshould not have a degrading effect.

Preferably, between the method steps a) and b), between the method stepsb) and c) and between the method steps c) and c2), the obtainedmicroparticles are washed in order to keep the content of removableconstituents of the previous step low in the following step.

As a result, in accordance with the invention, with the use ofpolyimides as base polymer and a treatment or post treatment of theparticulate start-out particles with special aqueous amine-containingsolutions, micro-particles or, respectively carrier matrices with acomplex property profile can be obtained.

When it is referred to a polyimide polymer not only pure polyimides butalso compound classes such as poly(amideimides), poly(ester-imides),poly(ether-imides) etc., are meant. In accordance with the invention, itis only necessary that the polymer designated here as polyimide containsin the polymer chain a sufficient number of imide groups in the mainchain. As a result, each polymer which includes this imide function insufficient numbers can be transformed by the method according to theinvention to microparticles with the complex property characteristicsdescribed above. As a preferred number of imide groups, it has beenfound that this polyimide polymer should have at least one imide groupper base unit with a mole mass of less than, or equal, 1000 g/mol.However, preferably polymers of “pure” polyimides or respectively,mixtures thereof are used, wherein, depending on circumstances, polymeradditives may be added. The polyimide polymer used and also the additiveor the additives which may be present, must be soluble in a commonsolvent or a mixture of solvents, in order to make the manufacture ofthe micro-particle out of the dissolved state possible. The solventmixture may include 2, 3, 4, or many solvents or, respectively, becomposed thereof.

As solvent for the manufacture of the polyimide solution or,respectively, the polymer solution, in principle, any solvent forpolyimides known to the person skilled in the art or, respectively, anysolvent mixture may be used, by which polymer solutions with a polymercontent of preferably 1 to 20 wt % can be produced. This range of 1 to20 wt % comprises all intermediate values and particularly allintermediate individual values, that is, consequently, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 wt %.

However, preferably solvents or solvent mixtures are used for themanufacture of polymer solutions which, with a phase inversion of thepolymer solution by the effects of a precipitation medium, lead at leastin the surface areas of the formed particles to a foam-like morphology.

The concentration in the polymer solution is preferably 5 to 15 wt %,which applies particularly to a spray process for the manufacture of theparticles. Under these conditions—depending on the selection of themanufacturing conditions and the manufacturing process—microparticleswith a particle diameter of 20 μm to 1000 μm are produced which havelittle swelling tendencies.

In the step c), the microparticles obtained in the step b) are treatedor, respectively, post-treated. The moist particles are treated with apreferably 1 to 10 wt % aqueous solution of an amine-containing modifierfor a period of 5 min. to 4 h, preferably 20 min to 2 h with or withoutstirring at a temperature of preferably 50 to 100° C., preferably 70 to95° C. As amine-containing modifier preferably aliphatic di- or,respectively, oligoamines or, respectively mixtures thereof are used.Particularly short-chain oliphatic di-, tri-, tetra-, or respectively,pentamines with primary and/or secondary and/or tertiary amino groupsare used.

The groups interconnecting the amine groups or, respectively, spacersare of an aliphatic nature and, consequently, alkyl groups which havepreferably 2, 3, 4 or 5 cations. As modifier preferablydiethylentriamine is used. With the use of this modifier preferablydiethylentriamine is used.

With the use of this modifier, the pore system particularly at thesurface of the particles is opened but also the pores in the interior ofthe particles are opened. As a result, the open-pore microparticlesaccording to the invention are formed which have a surface porositywhich corresponds practically to the porosity in the interior of theparticles to the porosity in the interior of the particles. At the sametime with this treatment, a covalent functionalization of all surfaceswith amine groups occurs. This covalent binding to microparticles occursby reaction of the imide groups with the amine groups of the modifierthereby forming the macromolecular structure.

If, nevertheless, a higher number of functional groups of the same ordifferent chemical nature, which can potentially be activated, isdesired, in another treatment step, that is, in the method step c2) afurther treatment can be provided. In this case, a functionalizationsolution is used with a further modifier. This further modifier may becomposed of a combination of at least two functional groups permolecule, wherein at least one of the functional groups is an aminegroup. This compound is therefore at least a di-functional compound.However, compounds with very different chemical structures can be used.As modifier furthermore, a mixture of 2, 3 or many such compounds can beused. Compounds can be used as modifiers as they are described forexample in applicants DE-A 101 11 685. These compounds are of monoaminenature and have a slight tendency to open the pore system uponperforming the method steps according to the invention. They canfurthermore be easily activated. As further functional groups which canbe activated, preferably hydroxyl and/or carboxyl groups can be used. Asanother modifiers, particularly alcohol amines, amino acids, iminedioacetic acid, phenylene diamine, and polyamines of the type of theethylene-imine may be used.

These amine groups which are bound covalently and are present in largenumbers can be activated in a simple manner and can be used already inthis form as absorption media, or, respectively, after binding ofaffinity ligands, for adsorption separations. Furthermore, these aminegroups can be converted into other functional groups such as carboxyl-,hydroxyl-, or aldehyde groups, which, as is known, represent suitablefunctions for the binding of ligands.

Subsequently, the microparticles produced in accordance with theinvention are intensely washed in a known manner in order to remove allthe components of the manufacturing process which are not covalentlybound, with the exception of water. If desired the microparticles cansubsequently also be dried, which occurs preferably at room temperature.The microparticles produced in accordance with the invention have such ahigh stability with respect to drying processes that, during a milddrying process (drying at room temperature), the overall porosity of theparticles changes only slightly.

The temperature conditions and the length of the treatment in theprocess steps c) and c2) are preferably the same but they may bedifferent.

In summary, it can be said that the microparticles according to theinvention are swell stable. They have only a small flow resistance andhave a highly porous structure with a high number of surface pores withpore diameters of more than 10 nm. As a result, the porosity of thesurface layers of the microparticles according to the invention iscomparable with the porosity in the particle interior.

The surface areas (inner and outer surfaces) of the microparticles areprovided with a large number of functional groups which can be easilyactivated and which therefore represent easily activatable bindinglocations for affinity ligands. Furthermore, a steam sterilization ofthe microparticles according to the invention is possible withoutnoticeable property changes.

Subject of the invention is also a process for the manufacture of themicroparticles according to the invention and the use thereof asadsorption structures for adsorptive separation. These microparticlesare preferably used in combinations with peptide ligands asimmuno-adsorbers.

Included in the microparticles according to the invention are alsomicroparticles to which the ligands of various different types arebound, wherein these bindings may be covalent or of another type.

Below, the invention will be described in detail on the basis ofexamples for the production of the microparticles according to theinvention and their properties. The polyamide used in the examples is apolyetherimide (PEI) of the Ultem 1000-type (General Electric Corp.).The manufacture of the start-out microparticles is performed for exampleby a spray process with subsequent precipitation-induced phase inversionin water. The percent values indicated are mass % if not otherwisenoted.

For the characterization of the microparticles according to theinvention, the following characterization techniques were used.

1. The particle diameter was determined by microscope examination usinga graduated measuring plate, while the particles were moist wherein atleast 200 particles were measured.

2. The overall porosity was determined gravimetrically. To this end, aparticle bed of different bed volume was defined by evacuation,conditioned and the weight of the removed moist and the dry samples wasdetermined. The overall porosity [%] resulted from$P_{overall}\quad\frac{W_{moist} - W_{dry}}{W_{dry}} \times 100$

This overall porosity comprises the pore volume and the volume of theattached water.

3. The content of the amine functions was determined by means ofcoloring agent adsorption using acid orange II. After being charged thecoloring agent-laden particles were washed intensely (24 h) at a pH=3,the coloring agent was desorbed at a pH=12 and the color solution wasmeasured spectroscopically at a wavelength of 492 nm.

4. The structure of the particle surface was determined before and afterthe treatment by raster electron microscopy. The samples which weredried after alcohol exchange were sputtered with gold/palladium.

EXAMPLE 1

Manufacture of the Microparticles/Carrier Matrix 1:

A solution of PEI was prepared dissolved in a solution mixtureconsisting of 96% N-methylpyrrolidon and 4% water by dissolution for 4 hat 80° C. After cooling, the solution was filtered and used in thisstate for the manufacture of microparticles by a spray process using aspray nozzle with an opening diameter of 300 μm.

The solution was sprayed with the aid of nitrogen via an air gap of 8 cminto a precipitation medium consisting of water. After the manufacture,the microparticles were washed with water several times and finallytreated for 1 h at 100° C. and then again washed.

The particles obtained were characterized with respect to particlediameter, overall porosity, bed volume per g dry particles and themorphological appearance of the particle surface.

The following characteristic data were determined: Particle diameterrange: 210-330 μm Overall porosity: 81.4% Bed volume/g of dry particles:8.0 ml

EXAMPLES 2 TO 6

The micro-particles produced in example 1 were post treated with a 4%aqueous diethlenetriamine (DETA) solution at 90° C. for differentperiods. In order to realize this primary treatment the followingexperimental way was selected:

Microparticles of the example 1 with a bed volume of 25 ml weresedimented in a temperature-controlled container, the sediment wascarefully removed. 40 ml of a 4% aqueous DETA solution was added at roomtemperature and placed into a shaking machine. After completion of thesuspension, the suspension was heated by a thermostatically controlledheater, preheated to 90° C. and treated while being subjected toshaking. The point in time when the heater was connected was defined astreatment time 0.

The treated particles had the characteristics as shown in table 1. TABLE1 Characteristic data of the examples 2-6 Particle diameter OverallAmine content Treatment range porosity [n mol/mg - Example time [min][μm] [%] dry particles] 1 0 210-330 81.4 0 2 30 — 83.1 78 3 60 210-33086.7 125 4 90 210-330 88.8 173 5 105 — 91.4 211

In accordance with the data determined, the particle diameter rangechanged—if at all—only within the error range of the measurement,whereas the overall porosity increased as a result of the treatment(hydrophilization). Also, in a controlled adjustable way, a high contentof amine functions were bound during the treatment to the membrane.

As a result, the overall porosity provided by pores with a pore diameterof more than 10 nm was increased by the treatment in comparison withuntreated particles.

EXAMPLES 7 AND 8

The microparticles as manufactured in Example 1 were, in accordance withExample 2, post-treated with a 4% aqueous diethylenetriamine (DETA)solution at 90° C. for 30 min, cooled and washed with distilled wateruntil the wash water was neutral. Subsequently, a second post treatmentwas performed under the same conditions with the difference that a 4%aqueous polyethyleneimine solution (M_(n)=600 D; M_(w)=800 D) was usedas modifier solution and the post treatment was performed for 10 andrespectively, 30 min.

The treated particles had the characteristics as shown in Table 2. TABLE2 Characteristic data of the example 7 and 8 Amine content TreatmentOverall porosity [nmol/mg - dry Example time [min] [%] particles] 2 3083.1 78 7 30 + 10 83.1 127 8 30 + 30 83.3 131

Under these post treatment conditions, the content of amine groups couldbe increased without a noticeable increase in the overall porosity ofthe base particle.

EXAMPLE 9

The microparticles produced in Example 1 were post-treated in accordancewith example 2 with a 4% aqueous diethylenetriamine (DETA) solution at90° C. for 30 min, cooled and washed with distilled water until the washwater was neutral. Subsequently, a second post treatment was performedunder the same conditions with the differences that a 4% aqueouspolyethyleneimine solution (M_(M)=600 D; M_(w)=800 D) was used asmodifier solution and the post treatment was performed for 10 min. Afterthis second post treatment, the neutral washed particles were dried atroom temperature and subsequently again moistened.

The treated particles had the characteristics as shown in table 3. TABLE3 Characteristic data of the examples 7 and 9: Amine content TreatmentOverall porosity [nmol/mg - dry Example time [min] [%] particles] 7 30 +10 83.1 127 9 30 + 30 78.1 127

With the drying the overall porosity was only slightly reduced. Theamine content is identical within the measuring error of thedetermination technique. Consequently, the particles can be dried atroom temperature without performance losses.

EXAMPLE 10

The microparticles as produced in example 1 were, as in example 2post-treated with a 4% aqueous diethylenetriamine (DETA) solution at 90°C. for 30 min, cooled, and then washed with distilled water until thewater was neutral. A second post treatment followed under the sameconditions, however with the differences that a 4% aqueouspolyethyleneimine solution (M_(n)=600 D; M_(w)=800 D) was used asmodifier solution and the post treatment was performed for 30 min. Afterthe second post treatment, the neutral washed particles were sterilizedfor 30 min at 121° C. in water using steam. TABLE 4 Characteristic dataof the example 8 and 10: Amine content Treatment Overall porosity [nmol/mg - dry Example time [min] [%] particles] 8 30 + 30 83.3 131 1030 + 30 83.1 101

With the drying procedure, the overall porosity was not reduced. Theamine content became slightly smaller apparently as a result of thefollowing reaction. Consequently, the particles can be steam-sterilizedwithout losses in performance.

EXAMPLE 11

The particles as produced and characterized in the example 1 and 2 wereexamined concerning compression stability with the passage of a PEGsolution consisting of 0.2907 g PEG MG=2 Mio Dalton and 0.2907 g PEGMG=4 Mio Dalten, dissolved in 1 liter water. This solution hadapproximately a viscosity, which was comparable to the viscosity a humanplasma. The pressure loss/pressure increase depending on the flowvelocity is based on a bed height of 3 cm. The measuring arrangementpermits pressure differences of maximally 2 bar to be determined safely.For comparison, Sephiarose® type CL-4B was included in the examinationas a swell-porous carrier and Eupergit® type 250 L (aminated) wasincluded as permanent-porous carrier.

The data of the measurements are represented in FIG. 1.

The results show that permanent-porous carrier matrices had asignificantly improved compression stability. Whereas Sepharose® wascompacted already at a flow speed of 120 an/h to such an extent thefurther flow was practically prevented the particles of the example 1and particularly of the example 2 were found to be significantly morecompression-resistant than Sepharose and moderately more compressionresistant then Eupergit.

1. Polyamide microparticles obtained by the following method steps: a) apolymer solution of at least one solvent is produced in a known manner,b) the polymer solution is converted to microparticles by spraying orthermal phase inversion, c) the microparticles obtained in step b) aretreated with an aqueous functionalization solution including an aminecontaining modifier at a raised temperature with or without stirring,and d) the obtained modified microparticles are washed in a way knownper se and, if appropriate, dried.
 2. Polyimide microparticles accordingto claim 1, wherein after the process step b) the following additionalprocess steps are performed: c2) the microparticles obtained after step2) are treated after removal of the amine-containing modifiers of theprocess step b) with an aqueous functionalization solution, whichcontains at least a further modifier, at a raised temperature with orwithout stirring, wherein the further modifier consists of at least onecompound with at least two functional groups per molecule of which oneis an amino group.
 3. Polyimide microparticles according to claim 1,wherein at least one of the following process steps are employed: i) inthe step a) a polymer solution with a polymer content of 1 to 20 wt %,particularly 5 to 15 wt % is produced, ii) in the step c) afunctionalization solution with a modifier content of 1 to 10 wt % isused, iii) the treatment with the functionalization solution in the stepc) is performed within a period 5 min to 4 hours, and iv) the treatmentwith the functionalization solution in step c) is performed at atemperature of 50 to 100° C.
 4. Polyimide microparticles according toclaim 1, wherein as the polyimide polymer for the manufacture of thepolymer solution in the step a), pure polyimides, poly(amide-imides),poly(ester-amides) and poly(ether-imides) are used.
 5. Polyimidemicroparticles according to claim 4, wherein the polyimide-polymer usedhas at least one imide group per base unit with a mole mass of not morethan 1000 g/mol.
 6. Polyimide microparticles according to claim 1,obtainable in that as amine containing modifier in the step c) analiphatic diamine or an aliphatic oligoamine or a mixture of diamines oroligo amines is used.
 7. Polyimide microparticles according to claim 6,wherein as diamine or oligoamines, triamines, tetra amines andpentamines with at least one of primary, secondary and tertiary aminogroups, particularly diethylenetriamine are used wherein the groupsinterconnecting the amine groups are alkylene groups with 2 to 5 Catoms.
 8. Polyimide microparticles according to claim 1, wherein asadditional modifier in the step c2) a compound is used which includes atleast a hydroxyl- and/or carboxyl group in addition to an amine group,and a diamine of aromatic nature, particularly alcohol amines, aminoacids, immuno diacetic acid, phenyl diamine and polyamines of the typeof the ethylene imines, or a mixture thereof.
 9. A method ofmanufacturing polyimide microparticles, comprising the following steps:a) a polymer solution of at least one solvent is produced in a knownmanner, b) the polymer solution is converted to microparticles byspraying or thermal phase inversion, c) the microparticles obtained instep b) are treated with an aqueous functionalization solution includingan amine containing modifier at a raised temperature with or withoutstirring, and d) the obtained modified microparticles are washed in away known per se and, if appropriate, dried.
 10. The use of polyimideparticles according to claim 1 as adsorbents and for adsorptiveseparations, particularly in combination with peptide-liquids asimmuno-adsorber for immunoglobuline.